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OXSR1

Serine/threonine-protein kinase OSR1 · UniProt O95747

Round 2 corrected Audit flag: wrong gene
Length
527 aa
Mass
58.0 kDa
Annotated
2026-04-29
130 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OXSR1 (OSR1) is a STE20-family serine/threonine kinase that functions as the central relay in the WNK signaling cascade controlling cation-chloride cotransporter activity and ion homeostasis. WNK1/WNK4 phosphorylate OSR1 at T-loop residue Thr185 to activate it, and the scaffold protein MO25 amplifies OSR1 kinase activity ~100-fold; OSR1 recognizes both its upstream activators and downstream substrates through RFXV/RxFxV motifs that dock into a structurally defined groove on its conserved C-terminal (CCT) domain (PMID:16083423, PMID:16669787, PMID:17721439, PMID:21423148). Activated OSR1 directly phosphorylates and stimulates Na⁺-K⁺-2Cl⁻ cotransporters (NKCC1, NKCC2) and NCC while inhibiting K⁺-Cl⁻ cotransporters (KCCs), thereby coordinating renal salt reabsorption and K⁺ homeostasis—functions confirmed by in vivo genetic epistasis showing that WNK-resistant OSR1/SPAK knock-in mice abolish NCC phosphorylation and that double-knockout mice develop severe hypokalemia under K⁺ restriction (PMID:21486947, PMID:24393035, PMID:27068441). Beyond ion transport, OSR1 is essential for embryonic angiogenesis downstream of WNK1, as endothelial-specific OSR1 deletion phenocopies WNK1 loss and constitutively active OSR1 rescues vascular defects, and OSR1 phosphorylates Smad2/3 to promote TGF-β-driven epithelial-to-mesenchymal transition in breast cancer (PMID:23386621, PMID:33051597). OSR1 activity is additionally modulated by mTORC2-mediated Ser339 phosphorylation and by CUL4-DDB1-WDR3/WDR6-dependent ubiquitination that is relieved upon osmotic stress-induced S-motif phosphorylation (PMID:24191005, PMID:31614064).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Identification of the substrate-docking mechanism: OSR1 was shown to physically interact with NKCC1, NKCC2, and KCC3 via a C-terminal domain recognizing (R/K)FX(V/I) motifs, establishing how OSR1 selects its cotransporter substrates.

    Evidence Yeast two-hybrid, GST pull-down, and co-immunoprecipitation with NKCC/KCC cotransporters

    PMID:12386165

    Open questions at the time
    • Structural basis of CCT–RFXV interaction not yet resolved
    • Functional consequence of interaction (phosphorylation, activation) not demonstrated
  2. 2004 High

    Initial biochemical characterization established OSR1 as an osmotic stress-activated STE20-family kinase that phosphorylates PAK1 but does not activate canonical MAPK cascades, defining its distinct signaling niche.

    Evidence In vitro kinase assay, site-directed mutagenesis, osmotic stress activation in cells

    PMID:14707132

    Open questions at the time
    • Physiological relevance of PAK1-Thr84 phosphorylation unclear
    • Upstream activator identity not established
  3. 2005 High

    The upstream activation mechanism was solved: WNK1/WNK4 directly phosphorylate OSR1 at Thr185 in its T-loop to activate it, and OSR1/SPAK directly phosphorylate the N-terminal regulatory domains of NKCC1, NKCC2, and NCC, establishing the hierarchical WNK→OSR1→cotransporter cascade.

    Evidence In vitro kinase assays with phosphopeptide mapping and T185A/T185E mutagenesis; cell-based phosphorylation assays under hypotonic stress

    PMID:16083423 PMID:16263722

    Open questions at the time
    • Relative contributions of OSR1 vs SPAK to each cotransporter unknown
    • In vivo validation of the cascade pending
  4. 2006 High

    The CCT domain was defined as a dual-purpose docking module that binds RFXV motifs in both activators (WNK1/WNK4) and substrates (NKCC1) with nanomolar affinity, and WNK1–OSR1 complex formation was confirmed in cells with functional consequence for NKCC activity.

    Evidence In vitro kinase assays with CCT mutagenesis, peptide binding affinity measurements, co-immunoprecipitation, siRNA knockdown reducing NKCC activity

    PMID:16382158 PMID:16669787 PMID:16832045

    Open questions at the time
    • Atomic-resolution structure of CCT–RFXV complex not yet available
    • Mechanism for substrate vs. activator discrimination at single binding groove unknown
  5. 2007 High

    The crystal structure of the CCT domain bound to a WNK4-derived RFXV peptide revealed a novel fold with a surface groove, and showed that phosphorylation preceding the RFXV motif causes steric clash promoting dissociation—providing a structural basis for phosphorylation-dependent regulation of docking.

    Evidence X-ray crystallography with mutational validation

    PMID:17721439

    Open questions at the time
    • Full-length OSR1 structure unavailable
    • Structural model for how CCT domain communicates with kinase domain not resolved
  6. 2008 High

    Specific NCC phosphorylation sites (Thr46, Thr55, Thr60) targeted by SPAK/OSR1 were mapped, with Thr60 identified as a priming site required for efficient phosphorylation of the other sites and for NCC activation.

    Evidence In vitro kinase assay and mutagenesis in HEK293 and mpkDCT cells under hypotonic low-chloride conditions

    PMID:18270262

    Open questions at the time
    • Whether ordered phosphorylation mechanism applies to NKCC substrates not tested
  7. 2009 High

    The kinase domain crystal structure at 2.25 Å revealed a domain-swapped dimer in an inactive conformation, providing a structural framework for understanding OSR1 autoinhibition and activation.

    Evidence X-ray crystallography

    PMID:19177573

    Open questions at the time
    • Whether domain swapping occurs in vivo or is a crystallographic artifact unknown
    • Structure of active (phospho-Thr185) kinase domain not solved
  8. 2011 High

    MO25 was identified as a ~100-fold activator of OSR1 kinase activity, and genetic epistasis in WNK-resistant SPAK/OSR1 knock-in mice confirmed in vivo dependence of NCC phosphorylation on this cascade, definitively validating the WNK→OSR1/SPAK→NCC pathway in renal physiology.

    Evidence In vitro reconstitution with MO25, siRNA knockdown/rescue in cells; triple knock-in mouse model with phospho-NCC immunoblotting

    PMID:21321328 PMID:21423148 PMID:21486947

    Open questions at the time
    • Structural basis of MO25-mediated activation unknown
    • Whether MO25 regulation is tissue-specific not addressed
  9. 2012 High

    Multiple regulatory layers on OSR1 were discovered: SPAK-dependent localization of OSR1 to the apical membrane in DCT, PI3K/mTORC2-mediated Ser339 phosphorylation as a convergent activation input, aldosterone-driven circadian oscillation of WNK–OSR1–NCC, and ASK3 as an upstream suppressor—revealing OSR1 as an integrative signaling node.

    Evidence SPAK-KO mice with immunofluorescence; in vitro mTORC2 kinase assay with Sin1 siRNA; time-course immunoblotting with eplerenone in mice; ASK3-KO mice

    PMID:22977235 PMID:23044422 PMID:23250415 PMID:24191005

    Open questions at the time
    • Relative quantitative contributions of mTORC2 vs WNK phosphorylation to total OSR1 activity unknown
    • Whether circadian regulation extends beyond the kidney not tested
  10. 2012 High

    Genetic evidence from double-knockin ES cells established that SPAK/OSR1 are the only kinases essential for NKCC1 phosphorylation and revealed feedback regulation whereby loss of SPAK/OSR1 activity elevates upstream WNK1/WNK3 activity.

    Evidence SPAK/OSR1 double-knockin ES cells, NKCC1 activity assays, immunoblotting for WNK phosphorylation

    PMID:22032326

    Open questions at the time
    • Identity of the WNK feedback phosphatase or mechanism not determined
  11. 2013 High

    OSR1 was established as essential for embryonic cardiovascular development: endothelial-specific OSR1 deletion phenocopied WNK1 knockout vascular defects, and constitutively active OSR1 rescued angiogenesis in WNK1-null embryos, placing OSR1 as the critical downstream effector of WNK1 in vascular morphogenesis.

    Evidence Conditional knockout mice (Tie2-Cre), constitutively active OSR1 transgene rescue, embryonic phenotyping

    PMID:23386621

    Open questions at the time
    • Downstream vascular targets of OSR1 in endothelial cells not fully identified
    • Whether ion cotransporters mediate the angiogenic role unclear
  12. 2014 High

    The substrate repertoire was greatly expanded: OSR1 was shown to inhibit all KCC isoforms via direct phosphorylation, regulate Kir2.1/2.3 membrane localization via RxFxV docking, phosphorylate Smad2/3 to drive EMT and metastasis, and modulate ROMK1 and ClC-2 channels—broadening OSR1 from a cotransporter kinase to a versatile regulator of membrane transport and TGF-β signaling.

    Evidence In vitro kinase assays with KCC mutagenesis and knockin ES cells; Kir2.3 motif mutagenesis with siRNA; Smad2/3 co-IP and in vivo metastasis models; Xenopus oocyte electrophysiology for ROMK1 and ClC-2

    PMID:24393035 PMID:25322850 PMID:25323061 PMID:29581290 PMID:33051597

    Open questions at the time
    • Physiological contexts for many of these substrates not validated in vivo
    • Direct phosphorylation sites on Kir2.1/2.3, ROMK1, and ClC-2 not mapped
  13. 2016 High

    SPAK/OSR1 double-knockout mice revealed functional redundancy between the two kinases in K⁺ homeostasis: only combined loss caused severe hypokalemia and failure to phosphorylate NCC under dietary K⁺ restriction.

    Evidence SPAK/OSR1 DKO mice, dietary K⁺ manipulation, plasma K⁺ measurement, phospho-NCC immunoblotting

    PMID:27068441

    Open questions at the time
    • Tissue-specific non-redundant functions of OSR1 vs SPAK in other nephron segments not fully characterized
  14. 2019 Medium

    Two new regulatory mechanisms were defined: CUL4-DDB1-WDR3/WDR6-dependent ubiquitination of OSR1 that is abolished when the S-motif is phosphorylated during osmotic stress, linking WNK signaling to OSR1 protein stability; and WNK4-dependent formation of cytoplasmic WNK bodies containing SPAK/OSR1 in DCT during hypokalemia.

    Evidence AP-MS with pharmacological validation for CUL4 complex; immunofluorescence in WNK4-deficient and Kir4.1-KO mice with dietary K⁺ manipulation

    PMID:31614064 PMID:31736353

    Open questions at the time
    • Half-life measurements of OSR1 under different phosphorylation states not reported
    • Functional significance of WNK body localization for OSR1 activity quantitatively undefined
  15. 2023 High

    Re-evaluation with a new strain-specific phospho-NKCC2 antibody revealed that SPAK/OSR1 contribute only mildly to basal NKCC2 phosphorylation, in contrast to their dominant role in NCC regulation, implying alternative kinases phosphorylate NKCC2 in vivo.

    Evidence New pT96-NKCC2 antibody in WNK4⁻/⁻, SPAK⁻/⁻, OSR1⁻/⁻, and DKO mice with furosemide diuresis

    PMID:37881876

    Open questions at the time
    • Identity of the alternative NKCC2 kinase(s) unknown
    • Whether NKCC2 phosphorylation at other sites remains SPAK/OSR1-dependent not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of MO25-mediated OSR1 activation, the identity of kinases that phosphorylate NKCC2 independently of SPAK/OSR1, whether OSR1's non-cotransporter substrates (Smad2/3, Kir2.x, ROMK1) are physiologically relevant in vivo, and the mechanism by which OSR1 promotes angiogenesis independently of ion transport.
  • No full-length OSR1 structure or MO25–OSR1 complex structure available
  • In vivo validation of Smad2/3, Kir2.x, and ROMK1 as physiological OSR1 substrates lacking
  • Molecular targets downstream of OSR1 in endothelial angiogenesis unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 9
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-382551 Transport of small molecules 9 R-HSA-1266738 Developmental Biology 2
Partners
CAB39SLC12A1SLC12A2SLC12A3SMAD2STK39WNK1WNK4

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 WNK1 and WNK4 directly phosphorylate OSR1 at two sites: Thr185 in the T-loop of the catalytic domain and Ser325 in a C-terminal non-catalytic region. Phosphorylation of Thr185 is required for OSR1 activation; T185A mutation prevents activation by WNK1, while T185E (phosphomimetic) increases basal activity >20-fold. Mutation of Ser325 does not affect activity or WNK1-mediated activation. In vitro kinase assay, phosphopeptide mapping, site-directed mutagenesis The Biochemical journal High 16083423
2005 WNK1 phosphorylates OSR1 at an evolutionarily conserved serine residue outside the kinase domain, and mutation of this residue causes enhanced OSR1 kinase activity. SPAK and OSR1 directly phosphorylate the N-terminal regulatory regions of cation-chloride cotransporters NKCC1, NKCC2, and NCC. Phosphorylation of NCC is induced by hypotonic stress in cells. In vitro kinase assay, cell-based phosphorylation assays, hypotonic stress treatment The Journal of biological chemistry High 16263722
2002 OSR1 physically interacts with the cation-chloride cotransporters KCC3, NKCC1, and NKCC2 (but not KCC1 or KCC4) through the last 100 amino acids of OSR1. The binding motif on cotransporters consists of nine residues starting with (R/K)FX(V/I). Co-immunoprecipitation confirmed in vivo interaction of the related kinase SPAK with NKCC1 from mouse brain. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunohistochemistry The Journal of biological chemistry High 12386165
2006 OSR1 exists in a complex with WNK1 in cells, is activated by recombinant WNK1 in vitro, and is phosphorylated in a WNK1-dependent manner in cells. Depletion of WNK1 by siRNA reduces OSR1 kinase activity. Depletion of either WNK1 or OSR1 reduces NKCC activity in HeLa cells, placing both in a pathway required for NKCC function and volume regulation. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, NKCC activity assay Proceedings of the National Academy of Sciences of the United States of America High 16832045
2006 OSR1 possesses a 92-residue conserved C-terminal (CCT) domain that interacts with RFXV motifs present in both substrates (NKCC1) and activators (WNK1/WNK4). A peptide containing the RFXV motif binds the CCT domain with nanomolar affinity. Mutation of specific CCT domain residues inhibits OSR1-mediated phosphorylation of NKCC1 (which requires RFXV docking) but not of CATCHtide (which lacks RFXV). An intact CCT domain is required for WNK1 to efficiently phosphorylate and activate OSR1. In vitro kinase assay, peptide binding/affinity purification, CCT domain mutagenesis, CATCHtide peptide substrate development The Biochemical journal High 16669787
2006 OSR1 shares similar kinase properties to SPAK and similarly activates NKCC1 when co-expressed with WNK4 in Xenopus oocytes. OSR1 kinase activity is markedly inhibited by staurosporine and K252a, partially inhibited by N-ethylmaleimide and diamide, and unaffected by arsenite. Activity is stronger with Mn2+ than Mg2+. Xenopus oocyte expression system, in vitro kinase assay, pharmacological inhibitor profiling Molecular and cellular biology High 16382158
2007 Crystal structure of the CCT domain of OSR1 in complex with a WNK4-derived RFXV motif-containing peptide was solved, revealing a novel protein fold with a surface-exposed groove that mediates peptide binding. Phosphorylation of a Ser/Thr residue preceding the RFXV motif causes steric clash, promoting dissociation from the CCT domain. Mutational analysis confirmed that the groove interactions are required for binding to WNK1 and NKCC1. X-ray crystallography, mutational analysis, binding assays EMBO reports High 17721439
2008 SPAK and OSR1 phosphorylate human NCC at three conserved residues (Thr46, Thr55, Thr60) in response to WNK1 pathway activation by hypotonic low-chloride conditions. Efficient NCC phosphorylation requires docking interaction between an RFXI motif in NCC and SPAK/OSR1. Mutation of Thr60 to Ala markedly inhibits phosphorylation of Thr46 and Thr55 and abolishes NCC activation by hypotonic low-chloride treatment. In vitro kinase assay, site-directed mutagenesis, cell-based phosphorylation assay in HEK293 and mpkDCT cells Journal of cell science High 18270262
2004 OSR1 (oxidative stress-responsive 1) is a 58-kDa, 527-amino acid STE20 family kinase widely expressed in mammalian tissues. Endogenous OSR1 is activated specifically by osmotic stresses (notably sorbitol, and to a lesser extent NaCl). OSR1 does not activate JNK, p38, ERK2, or ERK5. OSR1 phosphorylates PAK1 at Thr84 in its N-terminal regulatory domain; T84E substitution reduces PAK1 activation by Cdc42, suggesting OSR1 modulates G-protein sensitivity of PAK. Two-hybrid screen, in vitro kinase assay, site-directed mutagenesis, osmotic stress activation assays The Journal of biological chemistry High 14707132
2009 Crystal structure of the OSR1 kinase domain was solved at 2.25 Å resolution, revealing a domain-swapped dimer in an inactive conformation in which the P+1 loop and αEF helix are swapped between dimer-related monomers. Structural integrity of chemical interactions is preserved in the domain-swapped interfaces. X-ray crystallography (2.25 Å resolution) Protein science High 19177573
2011 MO25α and MO25β bind to OSR1 (and SPAK) and induce ~100-fold activation of their kinase activity, dramatically enhancing phosphorylation of ion cotransporters NKCC1, NKCC2, and NCC. siRNA-mediated reduction of MO25 in mammalian cells inhibits phosphorylation of endogenous NKCC1 at SPAK/OSR1-dependent sites, rescued by re-expression of MO25α. MO25 associates with OSR1 in a manner analogous to its interaction with the STRAD pseudokinase. In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, rescue experiments, surface plasmon resonance The EMBO journal High 21423148
2011 In vivo genetic evidence confirms that NCC phosphorylation by the WNK4 D561A mutation is almost completely abolished in triple knock-in mice where both SPAK (T243A) and OSR1 (T185A) cannot be activated by WNK kinases. This establishes that NCC phosphorylation in vivo is dependent on the WNK-OSR1/SPAK cascade, and that PHAII caused by WNK4 D561A requires OSR1/SPAK activation. Genetic knock-in mouse model, immunoblotting for phospho-NCC, blood pressure and metabolic measurements Journal of cell science High 21486947
2011 SPAK/OSR1 directly phosphorylate NKCC2 isoforms at Thr95, Thr100, Thr105 (and possibly Ser91) via interaction with an RFQV docking motif on NKCC2. A SPAK-OSR1-independent kinase (possibly AMPK) phosphorylates Ser130. Phosphorylation of Thr105 and Ser130 plays the most important role in stimulating NKCC2 activity. Unlike NCC, NKCC2 is constitutively membrane-localized and not regulated by SPAK/OSR1-dependent membrane translocation. In vitro kinase assay, cell-based phosphorylation assay, site-directed mutagenesis, NKCC2 isoform analysis Journal of cell science High 21321328
2012 SPAK/OSR1 double-knockin ES cells (where both kinases cannot be activated by WNK1) show no phosphorylation or activation of NKCC1, providing genetic evidence that SPAK/OSR1 are essential for NKCC1 function. WNK1 and WNK3 activities are markedly elevated in these knockin cells, demonstrating that SPAK/OSR1 feedback to influence upstream WNK activity. Phosphorylation of WNK1 Ser1261 is unaffected, indicating it is not a SPAK/OSR1 substrate. Double-knockin ES cells, immunoblotting, NKCC1 activity assay, in vitro kinase assay The Biochemical journal High 22032326
2012 In the kidney, OSR1 activity is dependent on SPAK in the distal convoluted tubule (DCT) but not the thick ascending limb (TAL). In SPAK-null mice, OSR1 becomes largely inactive, displaced from MO25α and NCC at the apical membrane, and redistributes to dense cytoplasmic punctate structures containing WNK1. This demonstrates that SPAK is required for proper OSR1 localization and activity in DCT, and that OSR1 apical membrane localization is functionally linked to NCC phosphorylation. SPAK knockout mice, immunofluorescence, subcellular fractionation, immunoblotting The Journal of biological chemistry High 22977235
2012 PI3K/mTORC2 activates OSR1 by phosphorylating it on Ser339. Inhibition of PI3K reduces OSR1 activation by osmotic stress, and depletion of Sin1 (mTORC2 component) decreases OSR1 activation by sorbitol and reduces NKCC activity in HeLa cells. Mutation of Ser339 eliminates mTORC2-dependent OSR1 phosphorylation, identifying a convergent regulatory node on OSR1 from the PI3K pathway. In vitro kinase assay (mTORC2 phosphorylates OSR1), pharmacological inhibition, siRNA knockdown of Sin1, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 24191005
2012 OSR1 participates in regulation of renal tubular phosphate transport via NaPiIIa. Coexpression of OSR1 in Xenopus oocytes significantly upregulates phosphate-induced currents in NaPiIIa-expressing oocytes. In osr1tg/(+) mice carrying a WNK-resistant OSR1, urinary phosphate excretion is increased and NaPiIIa protein abundance in brush border membrane is reduced, associated with elevated serum FGF23. Xenopus oocyte electrophysiology, mouse knock-in model, immunohistochemistry, confocal microscopy Kidney & blood pressure research Medium 23095210
2012 The phosphorylation levels of OSR1, SPAK, and NCC exhibit a diurnal rhythm in mouse kidney that correlates with active/rest periods. This circadian rhythm of the WNK4-OSR1/SPAK-NCC cascade is abolished by eplerenone (aldosterone receptor blocker), indicating aldosterone governs the circadian oscillation of this kinase cascade. Time-course immunoblotting in mice, pharmacological treatment with eplerenone Biochemical and biophysical research communications Medium 23044422
2012 ASK3 (apoptosis signal-regulating kinase 3) interacts with WNK1 and suppresses the WNK1-SPAK/OSR1 signaling pathway. Knockdown of ASK3 enhances SPAK/OSR1 activation, and ASK3 knockout mice show hyperactivation of SPAK/OSR1 in renal tubules and a hypertensive phenotype, positioning ASK3 as an upstream suppressor of the WNK1-SPAK/OSR1 pathway in response to osmotic stress. Co-immunoprecipitation (WNK1-ASK3 interaction), siRNA knockdown, ASK3 knockout mice, immunoblotting Nature communications High 23250415
2012 Estradiol treatment of newborn rat pups significantly increases protein levels of OSR1 (and SPAK) in the hypothalamus via a transcription-dependent mechanism. OSR1 knockdown by antisense oligonucleotides precludes estradiol-mediated enhancement of NKCC1 phosphorylation and diminishes estradiol-enhanced Ca2+ influx induced by GABAAR activation in embryonic hypothalamic cultures. In vivo neonatal rat treatment, immunoblotting, antisense knockdown, calcium imaging The Journal of neuroscience Medium 22238094
2013 WNK1 activates the OSR1 signaling cascade to regulate embryonic cardiovascular development. Global or endothelial-specific deletion of Osr1 in mice causes embryonic lethality at ~E11 with identical cardiovascular defects to WNK1 knockout (no mature large vessels in yolk sacs, defective angiogenesis, smaller cardiac chambers). Endothelial-specific expression of constitutively active OSR1 rescues angiogenesis and cardiac defects in global WNK1-null embryos, establishing OSR1 as an essential downstream effector of WNK1 in vascular development. Conditional knockout mice (Tie2-Cre), constitutively active OSR1 transgene rescue, embryonic phenotype analysis The Journal of biological chemistry High 23386621
2014 WNK-activated SPAK/OSR1 (in the presence of MO25) directly phosphorylates all KCC isoforms at Site-2 (Thr1048 in KCC3A) in vitro, promoting their inhibition. In ES cells lacking SPAK/OSR1 activity, endogenous KCC Site-2 phosphorylation is abolished and KCC3A activity is elevated. A Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation shows increased activity, confirming that SPAK/OSR1 phosphorylation inhibits KCC-mediated Cl- efflux. SPAK/OSR1 also phosphorylate KCCs at Site-3 (Thr5/Thr6) and Site-4 (Ser96). In vitro kinase assay with MO25, knockin ES cells lacking SPAK/OSR1 activity, 86Rb+ uptake assay, site-directed mutagenesis The Biochemical journal High 24393035
2014 WNK1-OSR1 signaling is required for HUVEC cord formation, chemotaxis, and invasion. OSR1 (but not SPAK) is specifically required for HUVEC chemotaxis and invasion, while SPAK is required for proliferation. OSR1 and WNK1 regulate the zinc-finger transcription factor Slug in endothelial cells. Constitutively active OSR1 rescues WNK1 deficiency, confirming OSR1 acts downstream of WNK1 in endothelial function. siRNA knockdown, cord formation assay, chemotaxis/invasion assay, gene expression analysis, HUVEC culture Proceedings of the National Academy of Sciences of the United States of America High 25362046
2014 OSR1 activates inward rectifier K+ channels Kir2.1 and Kir2.3 via an R-x-F-x-V/I motif variant (distinct from the canonical RFXV). Mutation of the RxFxV motif in Kir2.3 prevents its activation by OSR1. Both siRNA knockdown of OSR1 and chemical WNK inhibition disrupt NaCl-induced plasma membrane localization of Kir2.3, suggesting OSR1 enhances Kir2.1/Kir2.3 activity by increasing their plasma membrane localization. Kir4.1, which lacks this motif, is insensitive to OSR1. siRNA knockdown, pharmacological WNK inhibition, plasma membrane localization assay, site-directed mutagenesis of binding motif, Xenopus oocyte expression Proceedings of the National Academy of Sciences of the United States of America High 29581290
2014 OSR1 directly interacts with and phosphorylates Smad2 at Thr220 and Smad3 at Thr179 in the linker region. This phosphorylation causes nuclear translocation of Smad2/3 and enhances TGF-β1 autocrine signaling, driving epithelial-to-mesenchymal transition (EMT) and metastasis in breast cancer cells. OSR1 deletion in aggressive breast cancer cells inhibits EMT, and disruption of the OSR1-Smad2/3-TGF-β1 axis reduces metastasis in vitro and in vivo. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, nuclear translocation assay, loss-of-function (CRISPR/deletion), in vivo metastasis models Oncogene High 33051597
2014 OSR1 negatively regulates the creatine transporter SLC6A8 in Xenopus oocytes. Constitutively active (T185E)OSR1 reduces creatine transport, but catalytically inactive (D164A)OSR1 does not, indicating the effect requires OSR1 kinase activity. WNK-insensitive (T185A)OSR1 still negatively regulates SLC6A8, suggesting a WNK-independent mechanism for this substrate. Xenopus oocyte expression system, dual electrode voltage clamp, constitutively active and catalytically inactive OSR1 mutants Kidney & blood pressure research Medium 25531585
2014 Active OSR1 (T185E) downregulates ROMK1 K+ channel protein abundance at the cell membrane and channel activity in Xenopus oocytes; catalytically inactive (D164A)OSR1 has no effect. This is consistent with OSR1 kinase activity-dependent regulation of ROMK1 membrane trafficking. Xenopus oocyte expression, dual electrode voltage clamp, chemiluminescence-based surface protein assay Kidney & blood pressure research Medium 25322850
2014 Active OSR1 (T185E) negatively regulates ClC-2 Cl- channel activity in Xenopus oocytes. WNK1-insensitive inactive (T185A)OSR1 and catalytically inactive (D164A)OSR1 have no effect. Brefeldin A experiments suggest OSR1 does not accelerate ClC-2 retrieval from the membrane, indicating a different regulatory mechanism. Xenopus oocyte expression, dual electrode voltage clamp, brefeldin A treatment Kidney & blood pressure research Medium 25323061
2014 WNK1-OSR1 signaling promotes glioma cell migration. siRNA knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and abolishes NKCC1 regulatory phospho-activation, impeding regulatory volume increase in glioma cells. Temozolomide activates the WNK1/OSR1/NKCC1 pathway and enhances glioma migration, which is blocked by OSR1 siRNA knockdown. siRNA knockdown of OSR1, live cell imaging, microchemotaxis assay, cell volume and ion measurements, immunostaining Molecular cancer Medium 24555568
2014 OSR1 downregulates peptide transporters PEPT1 and PEPT2 by decreasing their maximum transport rate and reducing PEPT2 protein abundance at the cell membrane in Xenopus oocytes. The effect requires OSR1 kinase activity (T185E mimics, D164A and T185A are inactive), suggesting kinase-dependent membrane protein regulation. Xenopus oocyte electrophysiology, chemiluminescence surface protein assay, constitutively active and kinase-dead mutants Kidney & blood pressure research Medium 25531100
2014 Drosophila WNK-Fray (SPAK/OSR1 homolog) signaling cascade regulates K+ flux through Ncc69 (NKCC) in the renal tubule. Fray directly phosphorylates Ncc69 in vitro. A constitutively active Fray mutant rescues the wnk knockdown phenotype, establishing hierarchical WNK→Fray→NKCC signaling for hypotonicity-stimulated K+ flux, demonstrating evolutionary conservation of the WNK-SPAK/OSR1-NKCC cascade. Drosophila genetics, in vitro kinase assay, constitutively active mutant rescue, ion flux assay The Journal of biological chemistry High 25086033
2015 OSR1 upregulates the intestinal Na+-coupled phosphate cotransporter NaPi-IIb (SLC34A2) in Xenopus oocytes. Constitutively active (T185E)OSR1 and wild-type OSR1 (but not T185A or D164A mutants) significantly increase phosphate-induced currents and maximal transport rate, demonstrating that kinase activity is required. Combined SPAK+OSR1 coexpression shows an additive effect. Xenopus oocyte expression, dual electrode voltage clamp, constitutively active and kinase-dead mutants Kidney & blood pressure research Medium 26506223
2016 SPAK and OSR1 are essential for K+ homeostasis through their actions on the distal convoluted tubule. SPAK/OSR1 double knockout (DKO) mice develop severe hypokalemia on K+ restriction, unlike single KO mice. DKO mice fail to phosphorylate NCC under K+-restricted conditions, demonstrating that SPAK and OSR1 are redundant but essential effectors of the K+-sensing pathway that maintains plasma K+ through NCC activation. SPAK/OSR1 double knockout mice, dietary K+ restriction, plasma K+ measurement, phospho-NCC immunoblotting The Journal of physiology High 27068441
2017 Rafoxanide and closantel (antiparasitic agents) inhibit SPAK and OSR1 by binding to a highly conserved allosteric pocket on their C-terminal domains. This allosteric site influences kinase activity and can be exploited for inhibitor design. In silico screening, in vitro kinase assay, binding studies ChemMedChem Medium 28371477
2018 Verteporfin (photosensitizing clinical agent) inhibits SPAK and OSR1 kinases by binding to their kinase domains in an ATP-independent manner. In cells, verteporfin suppresses phosphorylation of NKCC1, a downstream physiological substrate of SPAK and OSR1. In vitro kinase assay, kinase panel screening, cell-based phosphorylation assay Chembiochem Medium 29999233
2019 The E3 ubiquitin ligase complex CUL4-DDB1-WDR3/WDR6 binds OSR1 in a phosphorylation-dependent manner via the S-motif (C-terminal serine phosphorylation site). S-motif phosphorylation following osmotic stress disrupts CUL4 complex binding, and OSR1 ubiquitylation is abolished under osmotic stress when its S-motif is phosphorylated, revealing a mechanism linking WNK-dependent S-motif phosphorylation to OSR1 proteostasis. Affinity pull-down, mass spectrometry, proteasomal and neddylation inhibitors, immunoblotting Chembiochem Medium 31614064
2019 In hypokalemia, WNK4 is the primary active WNK isoform that phosphorylates SPAK/OSR1 within cytoplasmic WNK bodies in the DCT. Phosphorylated SPAK/OSR1 is present both at the apical membrane and in WNK bodies within 12 h of K+ deprivation. In WNK4-deficient mice, larger WNK bodies form containing unphosphorylated WNK1, SPAK, and OSR1. WNK body formation in DCT requires sensing of plasma K+ via the Kir4.1 channel. Immunofluorescence microscopy, WNK4-deficient and Kir4.1 knockout mice, dietary K+ manipulation American journal of physiology. Renal physiology High 31736353
2012 OSR1 activity is required for LPS-stimulated migration of dendritic cells. In OSR1 knockin (WNK-resistant) dendritic cells, Na+/H+ exchanger activity and ROS production are elevated at baseline, but LPS fails to further increase them or stimulate migration. NKCC1 inhibition with furosemide increases NHE activity to levels similar to OSR1-deficient cells, suggesting OSR1-NKCC1 interaction regulates NHE activity. WNK-resistant OSR1 knockin mice, dendritic cell culture, FACS, fluorescent pH indicators, transwell migration assay American journal of physiology. Cell physiology Medium 22648948
2021 Pro-resolving FPR2 agonists (WKYMVm and annexin A1) induce phosphorylation of OSR1 at Ser339 via NADPH oxidase-dependent activation of PI3K and PKCδ. Blockade of NADPH oxidase prevents FPR2-induced OSR1(Ser339) phosphorylation, identifying NADPH oxidase→PI3K→OSR1(Ser339) as a pro-resolving signaling axis. Pharmacological NADPH oxidase inhibition, CRISPR/Cas9 p22phox knockout cells, phospho-specific immunoblotting Antioxidants Medium 33477989
2022 WNK1 HSN2 splice variant regulates neurite outgrowth through OSR1 activation and downstream GSK3β. The HSN2-OSR1/GSK3β signaling axis induces expression of LHX8, a key regulator of cholinergic neural function. HSANII patient-derived HSN2 mutants suppress OSR1 activation, LHX8 induction, and neurite outgrowth, and prevent interaction between wild-type HSN2 and GSK3β. Cell-based neurite outgrowth assay, OSR1 activation measurements, co-immunoprecipitation, LHX8 expression analysis, patient mutation analysis Scientific reports Medium 36151370
2005 OSR1 was identified through yeast two-hybrid screening as interacting with RELL1 (a RELT family member). OSR1 interacts with all three RELT family members (RELT, RELL1, RELL2) by co-immunoprecipitation and phosphorylates them in an in vitro kinase assay, identifying the RELT family as OSR1 substrates. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay Biochemical and biophysical research communications Medium 16389068
2012 Phosphorylation of NCC by OSR1/SPAK kinases decreases NCC ubiquitination. In mice, low-salt diet decreases NCC ubiquitination while high-salt diet increases it (inversely correlated with phosphorylation and membrane abundance). In COS7 cells, phospho-deficient NCC shows increased ubiquitination while phospho-mimicking NCC shows decreased ubiquitination for both total and surface NCC, establishing that OSR1/SPAK-mediated phosphorylation of NCC protects it from ubiquitin-mediated degradation. In vivo mouse models, COS7 cell expression, immunoprecipitation, ubiquitination assay, surface biotinylation Biochemical and biophysical research communications Medium 22846565
2023 Disruption of the WNK4-SPAK/OSR1 pathway using a new C57BL/6-specific pT96-NKCC2 antibody reveals that SPAK/OSR1 only mildly affects NKCC2 phosphorylation at baseline; NCC phosphorylation is strongly dependent on this pathway while NKCC2 is not. In WNK4-/- and SPAK/OSR1 double KO mice, pT96-NKCC2 is only slightly or not significantly reduced, suggesting alternative kinases phosphorylate NKCC2. New phospho-specific antibody, Wnk4-/-, Osr1-/-, Spak-/-, DKO mice, immunoblotting, furosemide diuresis assay American journal of physiology. Renal physiology High 37881876

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2005 High-throughput mapping of a dynamic signaling network in mammalian cells. Science (New York, N.Y.) 553 15761153
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. The Biochemical journal 432 16083423
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2005 WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. The Journal of biological chemistry 388 16263722
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2002 Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). The Journal of biological chemistry 318 12386165
2008 Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. Journal of cell science 317 18270262
2004 Phosphoproteomic analysis of the developing mouse brain. Molecular & cellular proteomics : MCP 291 15345747
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2006 Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. The Biochemical journal 261 16669787
2008 The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway. Journal of cell science 249 18843116
2009 Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell 243 19665974
2008 Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Developmental biology 236 18835385
2014 The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Science signaling 212 25028718
2014 The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. The Biochemical journal 175 24393035
2013 Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS. Nature methods 170 23455922
2008 Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney international 169 18800028
2008 SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. The Biochemical journal 163 18092945
1999 Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 162 10470851
2011 Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. Journal of cell science 161 21321328
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2006 WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proceedings of the National Academy of Sciences of the United States of America 158 16832045
2022 WNK kinases sense molecular crowding and rescue cell volume via phase separation. Cell 156 36318922
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2006 Characterization of SPAK and OSR1, regulatory kinases of the Na-K-2Cl cotransporter. Molecular and cellular biology 136 16382158
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2011 MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. The EMBO journal 121 21423148
2012 SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. The Journal of biological chemistry 118 22977235
2021 Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers. Nature genetics 116 34857952
2012 Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiological reviews 115 23073627
2012 SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. The Biochemical journal 114 22032326
2004 Caenorhabditis elegans OSR-1 regulates behavioral and physiological responses to hyperosmotic environments. Genetics 107 15166144
2012 Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension (Dallas, Tex. : 1979) 87 22949526
2005 Hypotonic shock mediation by p38 MAPK, JNK, PKC, FAK, OSR1 and SPAK in osmosensing chloride secreting cells of killifish opercular epithelium. The Journal of experimental biology 85 15767308
2007 Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO reports 81 17721439
2014 WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration. Molecular cancer 80 24555568
2004 Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. The Journal of biological chemistry 72 14707132
2014 Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis. Development (Cambridge, England) 69 24598167
2018 Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury. Stem cell research 64 30149291
2014 Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proceedings of the National Academy of Sciences of the United States of America 61 25362046
2012 ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney. Nature communications 61 23250415
2010 Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney. Biochemical and biophysical research communications 61 20175999
2011 Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. Journal of cell science 58 21486947
2006 Genome-wide analysis of SPAK/OSR1 binding motifs. Physiological genomics 55 17032814
2019 WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. American journal of physiology. Renal physiology 53 31736353
2016 SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule. The Journal of physiology 52 27068441
2012 The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1. Age (Dordrecht, Netherlands) 51 22864793
2006 SPAK and OSR1, key kinases involved in the regulation of chloride transport. Acta physiologica (Oxford, England) 51 16734747
2021 Knockdown of circ-FANCA alleviates LPS-induced HK2 cell injury via targeting miR-93-5p/OXSR1 axis in septic acute kidney injury. Diabetology & metabolic syndrome 50 33468219
2011 Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Current opinion in nephrology and hypertension 49 21610494
2013 WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. The Journal of biological chemistry 48 23386621
2012 Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/β-catenin-mediated lung specification in Xenopus. Development (Cambridge, England) 46 22791896
2012 OSR1-sensitive renal tubular phosphate reabsorption. Kidney & blood pressure research 44 23095210
2009 Crystal structure of domain-swapped STE20 OSR1 kinase domain. Protein science : a publication of the Protein Society 44 19177573
2012 Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clinical and experimental nephrology 43 22294159
2019 The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases. Aging and disease 42 31165006
2011 The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation. Developmental biology 42 21262216
2020 Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters. Frontiers in physiology 41 33192599
2014 Hypotonicity stimulates potassium flux through the WNK-SPAK/OSR1 kinase cascade and the Ncc69 sodium-potassium-2-chloride cotransporter in the Drosophila renal tubule. The Journal of biological chemistry 40 25086033
2017 Rafoxanide and Closantel Inhibit SPAK and OSR1 Kinases by Binding to a Highly Conserved Allosteric Site on Their C-terminal Domains. ChemMedChem 38 28371477
2011 A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function. Human molecular genetics 38 21821672
2006 Comparative expression pattern of Odd-skipped related genes Osr1 and Osr2 in chick embryonic development. Gene expression patterns : GEP 38 16554187
2015 Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. Journal of molecular and cellular cardiology 37 25986147
2012 Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination. Biochemical and biophysical research communications 36 22846565
2014 Curcumin-mediated oxidative stress resistance in Caenorhabditis elegans is modulated by age-1, akt-1, pdk-1, osr-1, unc-43, sek-1, skn-1, sir-2.1, and mev-1. Free radical research 35 24313805
2002 Molecular cloning and characterization of OSR1 on human chromosome 2p24. International journal of molecular medicine 35 12119563
2020 OSR1 phosphorylates the Smad2/3 linker region and induces TGF-β1 autocrine to promote EMT and metastasis in breast cancer. Oncogene 33 33051597
2012 WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. Biochemical and biophysical research communications 33 23044422
2009 Functional equivalence of the zinc finger transcription factors Osr1 and Osr2 in mouse development. Developmental biology 33 19389375
2005 Identification of RELT homologues that associate with RELT and are phosphorylated by OSR1. Biochemical and biophysical research communications 31 16389068
2017 OSR1 is a novel epigenetic silenced tumor suppressor regulating invasion and proliferation in renal cell carcinoma. Oncotarget 29 28404905
2017 Osr1 functions downstream of Hedgehog pathway to regulate foregut development. Developmental biology 28 28501478
2016 Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. Human molecular genetics 28 26744331
2014 Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. American journal of physiology. Renal physiology 27 24808538
2014 Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. Kidney & blood pressure research 27 25531585
2013 Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proceedings of the National Academy of Sciences of the United States of America 27 24191005
2012 Kinases SPAK and OSR1 are upregulated by estradiol and activate NKCC1 in the developing hypothalamus. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 22238094
2018 OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant. Proceedings of the National Academy of Sciences of the United States of America 26 29581290
2011 The Osr1 and Osr2 genes act in the pronephric anlage downstream of retinoic acid signaling and upstream of Wnt2b to maintain pectoral fin development. Development (Cambridge, England) 26 22129829
2024 Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 38353402
2021 Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases. Antioxidants (Basel, Switzerland) 25 33477989
2011 The nephrogenic potential of the transcription factors osr1, osr2, hnf1b, lhx1 and pax8 assessed in Xenopus animal caps. BMC developmental biology 25 21281489
2020 MicroRNA-25-3p suppresses epileptiform discharges through inhibiting oxidative stress and apoptosis via targeting OXSR1 in neurons. Biochemical and biophysical research communications 24 31954517
2020 WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension. Acta pharmacologica Sinica 24 32724175
2014 Regulation of ClC-2 activity by SPAK and OSR1. Kidney & blood pressure research 24 25323061
2014 SPAK and OSR1 dependent down-regulation of murine renal outer medullary K channel ROMK1. Kidney & blood pressure research 23 25322850
2019 Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2. The journal of pain 22 31085334
2018 WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium. American journal of physiology. Renal physiology 22 29923766
2014 Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1. Kidney & blood pressure research 22 25531100
2014 osr1 is required for podocyte development downstream of wt1a. Journal of the American Society of Nephrology : JASN 21 24722440
2022 WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy. International journal of molecular sciences 18 36292952
2018 The Photosensitising Clinical Agent Verteporfin Is an Inhibitor of SPAK and OSR1 Kinases. Chembiochem : a European journal of chemical biology 18 29999233
2020 Staurosporine and NEM mainly impair WNK-SPAK/OSR1 mediated phosphorylation of KCC2 and NKCC1. PloS one 17 32413057
2018 Odd-skipped related transcription factor 1 (OSR1) suppresses tongue squamous cell carcinoma migration and invasion through inhibiting NF-κB pathway. European journal of pharmacology 17 30244004
2023 Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation. American journal of physiology. Renal physiology 16 37881876
2021 High glucose-induced effects on Na+-K+-2Cl- cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII, and SPAK/OSR1. American journal of physiology. Cell physiology 16 33406028
2016 Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. PloS one 16 27442016
2022 Suppression of lncRNA GAS6-AS2 alleviates sepsis-related acute kidney injury through regulating the miR-136-5p/OXSR1 axis in vitro and in vivo. Renal failure 15 35793478
2021 Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice. Pflugers Archiv : European journal of physiology 15 33432425
2021 Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. International journal of molecular sciences 15 33513812
2021 The nephric mesenchyme lineage of intermediate mesoderm is derived from Tbx6-expressing derivatives of neuro-mesodermal progenitors via BMP-dependent Osr1 function. Developmental biology 15 34256037
2016 The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy. American journal of physiology. Renal physiology 15 27076645
2011 Generation of Osr1 conditional mutant mice. Genesis (New York, N.Y. : 2000) 15 21462293
2022 LncRNA ZFAS1 regulates the hippocampal neurons injury in epilepsy through the miR-15a-5p/OXSR1/NF-κB pathway. Metabolic brain disease 13 35751788
2022 osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2. Biomedicines 13 36359386
2020 Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease. Laboratory investigation; a journal of technical methods and pathology 13 33005011
2022 Long-term copper exposure caused hepatocytes autophagy in broiler via miR-455-3p-OXSR1 axis. Chemico-biological interactions 11 36372260
2012 OSR1-sensitive regulation of Na+/H+ exchanger activity in dendritic cells. American journal of physiology. Cell physiology 11 22648948
2012 The odd-skipped related genes Osr1 and Osr2 are induced by 1,25-dihydroxyvitamin D3. The Journal of steroid biochemistry and molecular biology 11 23238298
2019 The Cul4-DDB1-WDR3/WDR6 Complex Binds SPAK and OSR1 Kinases in a Phosphorylation-Dependent Manner. Chembiochem : a European journal of chemical biology 10 31614064
2015 Up-Regulation of Intestinal Phosphate Transporter NaPi-IIb (SLC34A2) by the Kinases SPAK and OSR1. Kidney & blood pressure research 10 26506223
2014 The OSR1 rs12329305 polymorphism contributes to the development of congenital malformations in cases of stillborn/neonatal death. Medical science monitor : international medical journal of experimental and clinical research 10 25164089
2022 WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway. Scientific reports 9 36151370